Hypocalcaemia

Contributed by Dr Amira Hegab, specialist registrar, and Dr Mark Vanderpump, consultant physician at the Royal Free Hampstead NHS Trust, London

1. Epidemiology and aetiology

Hypocalcaemia is the biochemical hallmark of functional hypoparathyroidism.

The concentration of calcium in the extracellular fluid is crucial for many physiological processes, and is maintained within narrow limits despite variations in dietary intake, the losses during pregnancy and lactation and the demands of the skeleton during growth.

Approximately 99 per cent of the total body calcium is found in the skeleton in the form of hydroxyapatite, leaving 1 per cent within the extracellular fluid and soft tissue. Forty per cent of serum calcium is protein-bound (albumin 80 per cent, globulin 20 per cent) and not biologically active.

Ten per cent is complexed to organic and inorganic acids. The remaining 50 per cent of the total serum calcium is in the ionised form, that is, biologically active. Therefore sudden changes in the distribution of calcium between the ionised and bound fractions can cause symptoms of hypocalcaemia.

Causes
Hypocalcaemia can result from failure to secrete parathyroid hormone (PTH), thus hypoparathyroidism.

It may be due to parathyroid destruction. This may be autoimmune (isolated or part of polyglandular autoimmune syndrome type 1a) or due to surgery (as a complication of thyroidectomy or following removal of all four parathyroid glands).

It may result from failure of parathyroid development. This may be isolated (X-linked) or found with other abnormalities such as DiGeorge's syndrome.

There may be a parathyroid hormone gene defect or calcium-sensing receptor mutations.

There could be problems with vitamin D levels: deficiency (although vitamin D deficiency alone is rarely a cause of hypocalcaemia), altered metabolism or production, caused for example by phenytoin or ketoconazole therapy.

There may be failure to release calcium from bone. Osteomalacia can result from vitamin D resistance, deficiency or renal failure.

Hypocalcaemia may be caused by inhibition of bone resorption. There may be an increased uptake of calcium in bone. It may be due to complexing of calcium from the circulation: alkalosis (causes increased albumin binding to calcium), acute pancreatitis or multiple blood transfusions (contain citrate).

2. Diagnosis

The clinical presentation of hypocalcaemia can range from an asymptomatic biochemical abnormality (usually with a serum calcium of 2-2.1mmol/l) to a severe condition (if levels are below 1.8mmol/l), with potentially life-threatening sequelae.

Neuromuscular irritability is a common presentation and can range from mild (paraesthesia and muscle cramps), to moderate (fatigue, anxiety, depression and irritability), to severe (carpopedal spasm, laryngospasm and focal/generalised seizures).

Tetany is uncommon unless the serum ionised calcium concentration falls below 1.1mmol/l (that is, when serum total calcium concentration is approximately 1.8-1.9mmol/l).

Trousseau's and Chvostek's signs may be elicited. Trousseau's sign is the occurrence of carpal spasm when a BP cuff is inflated above the patient's systolic BP for three minutes. Chvostek's sign is the contraction of the corner of the mouth, nose and eye ipsilateral to tapping the facial nerve.

Other less common features include dermatitis and hyperpigmentation of the skin, cataracts and arrhythmias.

Investigations
Measure serum levels of corrected calcium, phosphate, PTH, vitamin D, magnesium, and urea and creatinine.

Hypophosphataemia indicates either excess PTH secretion or low dietary phosphate intake. Hyperphosphataemia, however, in the absence of renal failure or increased tissue breakdown indicates either hypoparathyroidism (low/normal PTH) or pseudohypoparathyroidism (elevated PTH).

PTH concentrations must be interpreted with simultaneous serum calcium measurement. PTH is reduced in most patients with hypoparathyroidism and is elevated in patients with pseudohypoparathyroidism .

For vitamin D levels, usually 25-hydroxyvitamin D is measured. Vitamin D deficiency leads to the reduction of intestinal calcium absorption, resulting in hypocalcaemia.

Hypomagnesaemia causes hypocalcaemia by inducing PTH resistance. Urea and creatinine levels are measured to exclude renal failure.

3. Management

All patients with hypocalcaemia require a specialist opinion. The finding of a corrected calcium level lower than 1.9mmol/l requires urgent referral to the endocrine clinic.

Current management
Urgent treatment of acute or severe symptomatic hypocalcaemia occurs in a hospital setting with intravenous infusion of calcium (in the form of calcium gluconate). Vitamin D therapy is not required at that point.

Patients with asymptomatic or mild hypocalcaemia can be effectively treated with oral calcium and vitamin D. Oral calcium given in the amounts of 1-3g elemental calcium in three to four divided doses with meals ensures optimal absorption. Overall the goal is to maintain serum calcium in the low-to-normal range.

Vitamin D supplementation is usually in the form of ergocalciferol (calciferol, vitamin D2), alfacalcidol (1-alpha hydroxycholecalciferol) or calcitriol (1,25-dihydroxycholecalciferol).

The hypocalcaemia of hypoparathyroidism requires treatment with calciferol usually in the range of 50,000-100,000IU/day in order to achieve normocalcaemia.

In patients with chronic renal impairment the hydroxylated derivatives (alfacalcidol and calcitriol) should be prescribed (usual dosages are 0.25-1mu g daily).

Long-term monitoring
Serum calcium should be measured every three to six months to ensure levels are in the low-to-normal range.

The main side-effect of treatment is hypercalciuria, which can lead to nephrocalcinosis or nephrolithiasis.

New treatments
Daily injections of synthetic human PTH have been shown to normalise the concentration of calcium and phosphate effectively, while causing less hypercalciuria than does treatment with comparable doses of calcitriol.

Calcium supplements
Tablets

  • Cacit.
  • Calcium and ergocalciferol.
  • Calcium lactate.

Chewable tablets

  • Adcal-D3; Adcal.
  • Calceos.
  • Calcichew D3 Forte; Calcichew D3; Calcichew; Calcichew Forte.

Effervescent tablets/powders

  • Cacit D3.
  • Calcium gluconate.
  • Calfovit D3.
  • Sandocal 400; Sandocal 1000.

Syrup

  • Calcium-Sandoz.

 

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